[Federal Register Volume 59, Number 19 (Friday, January 28, 1994)]
[Unknown Section]
[Page ]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-1792]
[Federal Register: January 28, 1994]
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Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 310, et al.
Amendment of Final Monograph for Over-the-Counter Antihistamine Drug
Products; Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 341, and 369
[Docket No. 76N-052H]
RIN 0905-AA06
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use; Amendment of Final Monograph
for OTC Antihistamine Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the final
monograph for over-the-counter (OTC) antihistamine drug products to
include the ingredient doxylamine succinate. FDA is issuing this final
rule after considering extensive information concerning this ingredient
and the recommendations of its Nonprescription Drugs Advisory Committee
(NDAC), which met on June 28, 1993, to consider potential labeling for
doxylamine succinate regarding the results of toxicology testing
conducted under the National Toxicology Program (NTP). This final rule
is part of the ongoing review of OTC drug products conducted by FDA.
EFFECTIVE DATE: January 30, 1995.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-810), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5000.
SUPPLEMENTARY INFORMATION: In the Federal Register of September 9, 1976
(41 FR 38312), FDA published, under Sec. 330.10(a)(6) (21 CFR
330.10(a)(6)), an advance notice of proposed rulemaking for OTC cold,
cough, allergy, bronchodilator, and antiasthmatic drug products. In
that notice, the Advisory Review Panel on OTC Cold, Cough, Allergy,
Bronchodilator, and Antiasthmatic Drug Products (the Panel) recommended
that doxylamine succinate be generally recognized as safe and effective
(Category I) as an OTC antihistamine at a dosage level of 7.5 to 12.5
milligrams (mg) (41 FR 38312 at 38385 through 38387). At that time, the
agency concluded that doxylamine succinate should remain a prescription
drug at dosage levels above 7.5 mg because it causes a high incidence
of drowsiness compared to other OTC antihistamines (41 FR 38312 at
38313). Subsequently, after evaluating extensive data on the safety of
doxylamine succinate, the agency determined that doxylamine succinate
could be marketed OTC at the Panel's recommended dosage. In the Federal
Register of August 24, 1987 (52 FR 31892 at 31893 through 31903), the
agency proposed monograph status at dosages of 7.5 to 12.5 mg. No
comments were received in response to this proposal.
In 1991, the agency received a report of a study on doxylamine
succinate conducted by the National Center for Toxicological Research
(NCTR) (Ref. 1). The results of this study were under consideration
when the agency published the final monograph on OTC antihistamine drug
products on December 9, 1992 (57 FR 58356). Accordingly, the agency
deferred a decision on doxylamine succinate at that time.
The NCTR technical report concerns a 2-year carcinogenicity and
chronic toxicity study of doxylamine succinate in Fischer 344 rats and
B6C3F1 mice. The study was conducted under the auspices of the NTP. The
study was prompted by the National Cancer Institute's finding that
methapyrilene, a similar antihistamine, is a potent liver carcinogen in
the rat (Ref. 2). Methapyrilene was removed from the market in 1979.
The NCTR study on doxylamine succinate was reviewed by the agency's
Pulmonary-Allergy Drugs Advisory Committee (the P-A Committee) on June
13 and 14, 1991 (Ref. 3).
In the NCTR study (Ref. 1), doxylamine succinate was administered,
ad libitum, as an admixture in the feed to male and female rats at dose
levels of 0, 500, 1,000, or 2,000 parts per million (ppm) for 2 years.
Mice of both sexes received food containing dose levels of 0, 190, 375,
or 750 ppm. Each group contained 48 weanling animals per sex; the
animals were scheduled for sacrifice at the end of 104 weeks. An
additional group of animals (9 rats and 12 mice per sex) in each dose
group was sacrificed at the end of 65 weeks. There were no significant
treatment-related differences in survival in either rats or mice. In
rats, the highest doxylamine succinate dose group had final body
weights that were 22.8 percent (females) and 8.4 percent (males) lower
than controls. A number of nonneoplastic lesions was observed in rats,
including fatty change, degeneration, and hyperplasia of the liver and
increased cytoplasmic alteration in the salivary glands. In mice, there
was evidence of hepatotoxicity including hypertrophy, clear and mixed
cell foci, and, in females, fatty change. There also was a treatment-
related increase in ``atypical'' hepatocytes in male mice. Both male
and female mice had a dose-related increase in thyroid follicular cell
hyperplasia. There was a positive trend for increased incidence with
increasing dose for both hepatocellular adenomas and carcinomas in male
rats. When the incidence of adenomas and carcinomas was combined, the
statistical test was positive (p < 0.01)="" and="" the="" incidence="" in="" the="" highest="" dose="" group="" was="" significantly="" (p="">< 0.05)="" increased="" over="" that="" of="" controls.="" no="" treatment-related="" increase="" in="" neoplasms="" was="" found="" in="" female="" rats.="" although="" not="" statistically="" significant,="" one="" rat="" in="" each="" of="" the="" high="" dose="" groups="" of="" male="" and="" female="" rats="" was="" found="" to="" have="" a="" pineal="" gland="" tumor,="" which="" is="" an="" extremely="" rare="" neoplasm="" in="" rats.="" in="" mice,="" doxylamine="" succinate="" administration="" produced="" an="" increased="" incidence="" of="" hepatocellular="" adenoma="" in="" both="" males="" (p="">< 0.001)="" and="" females="" (p="">< 0.001).="" also,="" there="" was="" an="" increased="" incidence="" of="" follicular="" cell="" adenoma="" of="" the="" thyroid="" gland="" in="" male="" (p="">< 0.05)="" and="" female="" (p="">< 0.0001)="" mice.="" although="" the="" rodent="" tumorigenicity="" studies="" were="" positive,="" doxylamine="" succinate="" tested="" negative="" overall="" in="" in="" vitro="" tests="" for="" genotoxic="" activity="" (causing="" damage="" to="" deoxyribonucleic="" acid="" (dna)).="" based="" on="" the="" overall="" assessment,="" the="" tumorigenic="" responses="" observed="" in="" the="" rodent="" bioassays="" may="" relate="" to="" secondary="" mechanisms="" involving="" the="" induction="" of="" liver="" microsomal="" enzymes,="" cytotoxicity,="" cell="" proliferation,="" promotion="" of="" tumor="" potential="" in="" pre-existing="" susceptible="" cells,="" or="" other="" processes.="" such="" mechanisms="" may="" represent="" species-="" specific="" effects="" or="" threshold="" phenomena="" applicable="" to="" rodents="" (under="" the="" conditions="" of="" the="" bioassay),="" but="" these="" mechanisms="" are="" considered="" of="" questionable="" significance="" in="" humans.="" due="" to="" uncertainty="" concerning="" the="" relevance="" of="" these="" findings="" to="" human="" use,="" the="" agency="" asked="" its="" p-a="" committee="" and="" a="" number="" of="" consulting="" experts="" to="" evaluate="" the="" data="" and="" to="" advise="" the="" agency="" on="" whether="" doxylamine="" succinate="" should="" continue="" to="" be="" marketed="" otc.="" by="" a="" vote="" of="" five="" to="" one,="" the="" p-a="" committee="" concluded="" at="" its="" june="" 13="" and="" 14,="" 1991,="" meeting="" that="" doxylamine="" succinate="" is="" not="" likely="" to="" have="" human="" carcinogenic="" potential.="" again,="" by="" the="" same="" vote,="" the="" p-a="" committee="" recommended="" that="" doxylamine="" succinate="" could="" remain="" otc,="" but="" that="" consumers="" should="" be="" alerted="" that="" these="" data="" exist.="" the="" p-a="" committee="" discussed="" labeling="" as="" a="" preferred="" means="" of="" providing="" this="" information="" (ref.="" 3,="" pp.="" 175="" through="" 182).="" fda="" subsequently="" developed="" possible="" labeling="" that="" could="" be="" used.="" this="" labeling="" included="" the="" warning:="" ``use="" of="" this="" product="" may="" be="" hazardous="" to="" your="" health.="" this="" product="" contains="" doxylamine="" succinate="" which="" has="" been="" determined="" to="" produce="" tumors="" in="" laboratory="" animals.''="" the="" agency="" requested="" the="" views="" of="" a="" national="" trade="" association="" of="" otc="" drug="" manufacturers="" on="" this="" suggested="" warning="" (ref.="" 4).="" in="" response,="" the="" association="" asserted="" that="" such="" a="" warning="" would="" be="" inappropriate="" (ref.="" 5).="" the="" association="" stated="" that="" such="" a="" warning:="" (1)="" would="" not="" ensure="" safe="" and="" effective="" product="" use="" by="" consumers;="" (2)="" is="" not="" based="" on="" sound="" scientific="" data="" known="" to="" be="" relevant="" to="" the="" human="" condition;="" (3)="" is="" not="" understood="" and="" actionable,="" in="" a="" meaningful="" way,="" by="" consumers;="" and="" (4)="" might="" reduce="" the="" impact="" of="" other="" warnings="" and="" occupy="" scarce="" label="" space.="" the="" association="" argued="" that="" the="" proposed="" warning="" does="" not="" meet="" the="" criteria="" of="" section="" 502(c)="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" (21="" u.s.c.="" 352(c)).="" this="" part="" of="" the="" statute="" requires="" labeling="" information="" to="" be="" presented="" in="" ``terms="" as="" to="" render="" it="" likely="" to="" be="" read="" and="" understood="" by="" the="" ordinary="" individual="" under="" customary="" conditions="" of="" purchase="" and="" use.''="" the="" association="" contended="" that="" the="" proposed="" warning="" effectively="" shifts="" the="" burden="" of="" determining="" product="" safety="" from="" the="" agency="" to="" the="" consumer="" and="" then="" does="" not="" tell="" the="" consumer="" what="" action="" to="" take.="" in="" a="" subsequent="" communication="" (ref.="" 6),="" the="" association="" further="" argued="" that="" a="" warning="" statement="" in="" the="" labeling="" of="" doxylamine="" products="" is="" not="" justified="" because="" the="" scientific="" data="" do="" not="" suggest="" a="" significant="" risk="" to="" humans,="" that="" such="" a="" warning="" would="" be="" unprecedented,="" and="" that="" a="" label="" warning="" is="" not="" the="" appropriate="" means="" for="" disclosing="" this="" information.="" in="" 1992,="" the="" agency="" established="" a="" new="" advisory="" committee="" specifically="" for="" the="" review="" of="" otc="" drugs,="" the="" nonprescription="" drugs="" advisory="" committee="" (ndac).="" the="" agency="" asked="" ndac="" to="" consider="" the="" issue="" of="" a="" tumor="" statement="" in="" the="" labeling="" of="" otc="" drug="" products="" containing="" doxylamine="" succinate="" at="" its="" june="" 28,="" 1993,="" meeting.="" the="" agency="" presented="" a="" summary="" of="" the="" nctr="" data,="" possible="" labeling,="" and="" legal="" and="" compliance="" issues="" (ref.="" 7).="" other="" interested="" parties="" presented="" their="" positions.="" the="" agency="" asked="" ndac="" to="" consider="" the="" following="" questions:="" (1)="" should="" a="" labeling="" statement="" be="" used="" to="" inform="" consumers="" in="" place="" of="" other="" alternative="" approaches="" (no="" warning,="" prescription="" only="" status,="" removal="" from="" all="" marketing,="" etc.)?="" (2)="" is="" there="" a="" desirable="" risk-to-="" benefit="" relationship="" for="" labeling?="" (3)="" if="" the="" answer="" to="" both="" questions="" is="" yes,="" what="" information="" should="" be="" included="" in="" the="" labeling="" and="" what="" language="" should="" be="" used="" that="" would="" be="" easily="" understood="" by="" the="" average="" consumer?="" (4)="" how="" should="" information="" be="" presented="" to="" the="" consumer="" (i.e.,="" under="" the="" ``warning''="" or="" some="" other="" heading,="" visible="" at="" the="" point="" of="" purchase,="" on="" the="" immediate="" container,="" or="" in="" a="" package="" insert)="" and="" should="" the="" information="" indicate="" that="" the="" product="" could="" be="" ``hazardous''="" to="" health?="" after="" considering="" the="" available="" evidence,="" ndac="" voted="" unanimously="" (10="" to="" 0)="" to="" reaffirm="" the="" p-a="" committee's="" recommendation="" that="" doxylamine="" succinate="" remain="" otc.="" ndac="" also="" recommended="" (10="" to="" 0)="" that="" there="" be="" no="" specific="" statement="" about="" tumors="" in="" the="" labeling="" and="" urged="" fda="" to="" write="" a="" fully="" descriptive="" article="" on="" the="" subject="" in="" the="" ``fda="" consumer''="" magazine.="" the="" agency="" has="" considered="" the="" two="" advisory="" committees'="" recommendations="" and="" concludes="" that="" doxylamine="" succinate="" is="" safe="" and="" effective="" for="" otc="" use="" as="" an="" antihistamine.="" accordingly,="" the="" agency="" is="" including="" doxylamine="" succinate="" in="" the="" final="" monograph="" for="" otc="" antihistamine="" drug="" products.="" the="" agency="" is="" also="" developing="" an="" ``fda="" consumer''="" article="" and="" has="" issued="" a="" talk="" paper="" concerning="" the="" nctr="" findings="" in="" animals="" to="" inform="" consumers="" of="" these="" data="" and="" the="" uncertainty="" of="" their="" relevance="" to="" humans.="" references="" (1)="" department="" of="" health="" and="" human="" services,="" nctr,="" ``technical="" report="" for="" experiments="" 406="" and="" 407;="" chronic="" study="" of="" doxylamine="" in="" fischer="" 344="" rats="" and="" b6c3f1="" mice,''="" 1991,="" in="" otc="" vol.="" 04hfm,="" docket="" no.="" 76n-052h,="" dockets="" management="" branch.="" (2)="" lijinsky,="" w.,="" m.="" d.="" reuber,="" and="" b.="" n.="" blackwell,="" ``liver="" tumors="" induced="" in="" rats="" by="" chronic="" oral="" administration="" of="" the="" common="" antihistamine="" methapyrilene="" hydrochloride,''="" science,="" 209:817-819,="" 1980.="" (3)="" transcript="" of="" the="" june="" 13="" and="" 14,="" 1991,="" meeting="" of="" the="" fda="" pulmonary-allergy="" drugs="" advisory="" committee,="" coded="" rpt="" 5,="" docket="" no.="" 76n-052h,="" dockets="" management="" branch.="" (4)="" letter="" from="" w.="" e.="" gilbertson,="" fda,="" to="" r.="" w.="" soller,="" ndma,="" coded="" let="" 91,="" docket="" no.="" 76n-052h,="" dockets="" management="" branch.="" (5)="" letter="" from="" r.="" w.="" soller,="" ndma,="" to="" w.="" e.="" gilbertson,="" fda,="" coded="" c216,="" docket="" no.="" 76n-052h,="" dockets="" management="" branch.="" (6)="" letter="" from="" r.="" w.="" soller,="" ndma,="" to="" w.="" e.="" gilbertson,="" fda,="" coded="" c224,="" docket="" no.="" 76n-052h,="" dockets="" management="" branch.="" (7)="" transcript="" of="" the="" june="" 28,="" 1993,="" meeting="" of="" the="" fda="" nonprescription="" drugs="" advisory="" committee,="" vol.="" i,="" pp.="" 6-89,="" coded="" tr="" 2,="" docket="" no.="" 76n-052h,="" dockets="" management="" branch.="" the="" agency="" has="" examined="" the="" economic="" consequences="" of="" this="" final="" rule="" and="" has="" determined="" that="" it="" does="" not="" require="" either="" a="" regulatory="" impact="" analysis,="" as="" specified="" in="" executive="" order="" 12866,="" or="" a="" regulatory="" flexibility="" analysis,="" as="" defined="" in="" the="" regulatory="" flexibility="" act="" (pub.="" l.="" 96-354).="" this="" rulemaking="" for="" otc="" antihistamine="" drug="" products="" is="" not="" expected="" to="" have="" an="" impact="" on="" small="" businesses.="" doxylamine="" succinate="" remains="" available="" otc.="" no="" product="" reformulations="" will="" be="" required.="" some="" minor="" relabeling="" will="" be="" necessary="" to="" meet="" the="" conditions="" of="" the="" final="" monograph.="" manufacturers="" will="" have="" 1="" year="" to="" implement="" this="" relabeling.="" thus,="" the="" impact="" of="" the="" final="" rule="" appears="" to="" be="" minimal.="" therefore,="" the="" agency="" concludes="" that="" the="" final="" rule="" is="" not="" a="" major="" rule="" as="" defined="" in="" executive="" order="" 12866.="" further,="" the="" agency="" certifies="" that="" this="" final="" rule="" will="" not="" have="" a="" significant="" economic="" impact="" on="" a="" substantial="" number="" of="" small="" entities="" as="" defined="" in="" the="" regulatory="" flexibility="" act.="" the="" agency="" has="" determined="" under="" 21="" cfr="" 25.24(c)(6)="" that="" this="" action="" is="" of="" a="" type="" that="" does="" not="" individually="" or="" cumulatively="" have="" a="" significant="" effect="" on="" the="" human="" environment.="" therefore,="" neither="" an="" environmental="" assessment="" nor="" an="" environmental="" impact="" statement="" is="" required.="" the="" agency="" is="" removing="" the="" exemption="" for="" certain="" drugs="" limited="" by="" new="" drug="" applications="" (nda)="" to="" prescription="" sale="" in="" sec.="" 310.201(a)(13)="" (applicable="" to="" doxylamine="" succinate="" preparations)="" because="" most="" portions="" of="" that="" exemption="" are="" superseded="" by="" the="" requirements="" of="" the="" antihistamine="" final="" monograph="" (21="" cfr="" part="" 341).="" section="" 310.201(a)(13)="" does="" not="" apply="" to="" the="" use="" of="" doxylamine="" succinate="" as="" a="" nighttime="" sleep-="" aid,="" for="" which="" an="" nda="" is="" required="" for="" marketing.="" list="" of="" subjects="" 21="" cfr="" part="" 310="" administrative="" practice="" and="" procedure,="" drugs,="" labeling,="" medical="" devices,="" reporting="" and="" recordkeeping="" requirements.="" 21="" cfr="" part="" 341="" labeling,="" over-the-counter="" drugs.="" 21="" cfr="" part="" 369="" labeling,="" medical="" devices,="" over-the-counter="" drugs.="" therefore,="" under="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" and="" under="" authority="" delegated="" to="" the="" commissioner="" of="" food="" and="" drugs,="" 21="" cfr="" parts="" 310,="" 341,="" and="" 369="" are="" amended="" as="" follows:="" part="" 310--new="" drugs="" 2.="" the="" authority="" citation="" for="" 21="" cfr="" part="" 310="" continues="" to="" read="" as="" follows:="" authority:="" secs.="" 201,="" 301,="" 501,="" 502,="" 503,="" 505,="" 506,="" 507,="" 512-="" 516,="" 520,="" 601(a),="" 701,="" 704,="" 705,="" 721="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" (21="" u.s.c.="" 321,="" 331,="" 351,="" 352,="" 353,="" 355,="" 356,="" 357,="" 360b-360f,="" 360j,="" 361(a),="" 371,="" 374,="" 375,="" 379e);="" secs.="" 215,="" 301,="" 302(a),="" 351,="" 354-360f="" of="" the="" public="" health="" service="" act="" (42="" u.s.c.="" 216,="" 241,="" 242(a),="" 262,="" 263b-263n).="" sec.="" 310.201="" [amended]="" 2.="" section="" 310.201="" exemption="" for="" certain="" drugs="" limited="" by="" new-drug="" applications="" to="" prescription="" sale="" is="" amended="" by="" removing="" paragraph="" (a)(13)="" and="" reserving="" it.="" part="" 341--cold,="" cough,="" allergy,="" bronchodilator,="" and="" antiasthmatic="" drug="" products="" for="" over-the-counter="" human="" use="" 3.="" the="" authority="" citation="" for="" 21="" cfr="" part="" 341="" continues="" to="" read="" as="" follows:="" authority:="" secs.="" 201,="" 501,="" 502,="" 503,="" 505,="" 510,="" 701="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" (21="" u.s.c.="" 321,="" 351,="" 352,="" 353,="" 355,="" 360,="" 371).4.="" section="" 341.12="" is="" amended="" by="" adding="" new="" paragraph="" (h)="" to="" read="" as="" follows:="" sec.="" 341.12="" antihistamine="" active="" ingredients.="" *="" *="" *="" *="" *="" (h)="" doxylamine="" succinate.="" *="" *="" *="" *="" *="" 5.="" section="" 341.72="" is="" amended="" by="" revising="" the="" heading="" of="" paragraphs="" (c)(4)="" and="" (c)(6)(iii)="" and="" by="" adding="" new="" paragraph="" (d)(8)="" to="" read="" as="" follows:="" sec.="" 341.72="" labeling="" of="" antihistamine="" drug="" products.="" *="" *="" *="" *="" *="" (c)="" *="" *="" *="" (4)="" for="" products="" containing="" diphenhydramine="" citrate,="" diphenhydramine="" hydrochloride,="" or="" doxylamine="" succinate="" identified="" in="" sec.="" 341.12(f),="" (g),="" and="" (h).="" *="" *="" *="" *="" *="" *="" *="" *="" (6)="" *="" *="" *="" (iii)="" for="" products="" containing="" diphenhydramine="" citrate,="" diphenhydramine="" hydrochloride,="" or="" doxylamine="" succinate="" identified="" in="" sec.="" 341.12(f),="" (g),="" and="" (h).="" *="" *="" *="" (d)="" *="" *="" *="" (8)="" for="" products="" containing="" doxylamine="" succinate="" identified="" in="" sec.="" 341.12(h).="" adults="" and="" children="" 12="" years="" of="" age="" and="" over:="" oral="" dosage="" is="" 7.5="" to="" 12.5="" milligrams="" every="" 4="" to="" 6="" hours,="" not="" to="" exceed="" 75="" milligrams="" in="" 24="" hours,="" or="" as="" directed="" by="" a="" doctor.="" children="" 6="" to="" under="" 12="" years="" of="" age:="" oral="" dosage="" is="" 3.75="" to="" 6.25="" milligrams="" every="" 4="" to="" 6="" hours,="" not="" to="" exceed="" 37.5="" milligrams="" in="" 24="" hours,="" or="" as="" directed="" by="" a="" doctor.="" children="" under="" 6="" years="" of="" age:="" consult="" a="" doctor.="" *="" *="" *="" *="" *="" 6.="" section="" 341.90="" is="" amended="" by="" adding="" new="" paragraph="" (l)="" to="" read="" as="" follows:="" sec.="" 341.90="" professional="" labeling.="" *="" *="" *="" *="" *="" (l)="" for="" products="" containing="" doxylamine="" succinate="" identified="" in="" sec.="" 341.12(h).="" children="" 2="" to="" under="" 6="" years="" of="" age:="" oral="" dosage="" is="" 1.9="" to="" 3.125="" milligrams="" every="" 4="" to="" 6="" hours,="" not="" to="" exceed="" 18.75="" milligrams="" in="" 24="" hours.="" *="" *="" *="" *="" *="" part="" 369--interpretative="" statements="" re="" warnings="" on="" drugs="" and="" devices="" for="" over-the-counter="" sale="" 7.="" the="" authority="" citation="" for="" 21="" cfr="" part="" 369="" continues="" to="" read="" as="" follows:="" authority:="" secs.="" 201,="" 301,="" 501,="" 502,="" 503,="" 505,="" 506,="" 507,="" 701="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" (21="" u.s.c.="" 321,="" 331,="" 351,="" 352,="" 353,="" 355,="" 356,="" 357,="" 371).="" sec.="" 369.21="" [amended]="" 8.="" section="" 369.21="" drugs;="" warning="" and="" caution="" statements="" required="" by="" regulations="" is="" amended="" by="" revising="" the="" introductory="" text="" of="" the="" entry="" for="" ``antihistaminics,="" oral="" (phenyltoloxamine="" dihydrogen="" citrate,="" doxylamine="" succinate,="" and="" chlorothen="" citrate="" preparations)''="" to="" read="" ``antihistaminics,="" oral="" (phenyltoloxamine="" dihydrogen="" citrate="" and="" chlorothen="" citrate="" preparations).="" (see="" sec.="" 310.201(a)(4)="" and="" (a)(24)="" of="" this="" chapter.)''="" *="" *="" *="" *="" *="" dated:="" january="" 24,="" 1993.="" michael="" r.="" taylor,="" deputy="" commissioner="" for="" policy.="" [fr="" doc.="" 94-1792="" filed="" 1-27-94;="" 8:45="" am]="" billing="" code="" 4160-01-f="">